The long-range goal of this research is to elucidate the role of persistent mitochondrial DNA damage in neurodegeneration. There is now strong evidence that neurodegeneration in the majority of Parkinson's Disease cases is the result of the interplay of genetic differences with environmental exposures (gene-environment interactions), but neither the genes nor the environmental exposures involved are well understood. We are investigating the novel hypothesis that some important environmental toxins contribute to neurodegeneration by causing persistent mitochondrial DNA damage, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. Mitochondrial DNA is more sensitive than nuclear DNA to many insults, and there is no apparent repair pathway for handling mitochondrial DNA damage caused by important environmental genotoxins such as polycyclic aromatic hydrocarbons and ultraviolet radiation. We will test the role of such damage in causing neurodegeneration as a result of exposure during key developmental time periods. The specificity of this effect will be tested using innovative new transgenic strains of Caenorhabditis elegans. We will also test the hypothesis that specific genes involved in mitochondrial fusion and autophagy protect against such damage, taking advantage of the genetic and molecular tools available in Caenorhabditis elegans. Description of relevance to public health There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well.